IMMUNOHISTOCHEMICAL LOCALIZATION OF TRANSFORMING GROWTH-FACTOR-BETA-1IN RATS WITH EXPERIMENTAL SILICOSIS, ALVEOLAR TYPE-II HYPERPLASIA, AND LUNG-CANCER

Immunohistochemical localization of transforming growth factor-beta1, (TGF-beta1) was studied in the lungs of rats given crystalline silica or ferric oxide by single intratracheal instillation. Ferric oxide eli cited no progressive granulomatous reaction, no epithelial hyperplasia , and no lung tumors; no demonstrable reactivity to TGF-beta1 was obse rved. Silica induced a granulomatous reaction with progressive fibrosi s, adjacent alveolar type II hyperplasia, and alveolar carcinomas. Rab bit polyclonal antibodies to synthetic peptides corresponding to the f irst 30 amino acids of mature TGF-beta1, anti-LC (1-30), and anti-CC ( 1-30) were used for the localization of intracellular and extracellula r TGF-beta1. An antibody to a peptide corresponding to amino acids 266 -278 of the TGF-beta1 precursor sequence, anti-Pre (266-278), was used to detect the TGF-beta precursor and the latency-associated peptide. Intracellular mature TGF-beta (anti-LC) was demonstrated in fibroblast s and macrophages located at the periphery of silicotic granulomas and in fibroblasts adjacent to hyperplastic type II cells. Extracellular mature TGF-beta1, was localized in the connective tissue matrix of the granulomas and in the stroma of both hyperplastic type H cells and we ll-differentiated adenocarcinomas. Immunoreactivity to anti-Pre was lo calized, intracellularly, in hyperplastic alveolar type II cells and t heir proliferative lesions adjacent to granulomas, in adenomas, but no t in adenocarcinomas. The hyperplastic type II cells appear to be the sites of production and secretion of TGF-beta1, which may regulate the ir own growth and differentiation and mediate the production of extrac ellular TGF-beta1-associated matrix. The lack of reactivity to TGF-bet a1 precursor in the adeno-carcinomas is consistent with the loss of no rmal cellular differentiation and function. TGF-beta1 appears to have a pathogenetic role in silica-induced mesenchymal and epithelial lesio ns. The role of TGF-beta1 and other cytokines in silica-induced carcin ogenesis requires further investigation.